This invention relates to a novel composition of matter containing optically pure R(-) fluoxetine. This composition possesses potent antidepressant and appetite suppressant activity as a serotonin uptake inhibitor while avoiding the usual adverse effects associated with the racemic mixture of fluoxetine. Furthermore, this composition possesses potent activity as a serotonin uptake inhibitor which can be utilized in the treatment of migraine headaches, pain, psychoactive substance use disorders, and obsessive compulsive disorders, while avoiding the usual adverse effects associated with the racemic mixture of fluoxetine. Also disclosed are methods to treat depression, migraine headaches, pain, obsessive compulsive disorders, and psychoactive substance use disorders, and to effect appetite suppression in a human by administering pure R(-) fluoxetine. This also avoids the usual adverse effects associated with the racemic mixture of fluoxetine.
The active compound of this composition and method is an optical isomer of the compound fluoxetine which is described in U.S. Pat. Nos. 4,018,895 and 4,194,009 to Molloy, et al. Chemically, the R(-) isomer is (-)N-methyl-3-phenyl-3-[(.alpha.,.alpha.,.alpha.-trifluoro-p-tolyl)-oxy]-p ropylamine, herein after referred to as R(-) fluoxetine.
Many organic compounds exist in optically active forms, i.e., they have the ability to rotate the plane of plane-polarized light. In describing an optically active compound, the prefixes D and L or R and S are used to denote the absolute configuration of the molecule about its chiral center(s). The prefixes (+) and (-) or d and 1 are employed to designate the sign of rotation of plane-polarized light by the compound, with (-) or 1 meaning that the compound is levorotatory. A compound prefixed with (+) or d is dextrorotatory. For a given chemical structure, these compounds, called stereoisomers, are identical except that they are mirror images of one another. A specific stereoisomer may also be referred to as an enantiomer, and a mixture of such isomers is often called an enantiomeric or racemic mixture.
Stereochemical purity is of importance in the field of pharmaceuticals, where 12 of the 20 most prescribed drugs exhibit chirality. A case in point is provided by the L-form of propranolol, which is known to be 100 times more potent than the D-enantiomer.
Furthermore, optical purity is important since certain isomers may actually be deleterious rather than simply inert. For example, it has been suggested that the D-enantiomer of thalidomide is a safe and effective sedative when prescribed for the control of morning sickness during pregnancy and that the corresponding L-enantiomer is a potent teratogen.
Fluoxetine's primary use is in the treatment of depression, which along with mania falls under the heading of affective disorders. Mania and depression are characterized by changes in mood as the primary symptom.
Depression is characterized by feelings of intense sadness or pessimistic worry, agitation, self-deprecation, neurovegetative changes and symptoms such as insomnia, anorexia, and loss of drive, enthusiasm, and libido, and mental slowing. Among the more common treatments for depression are the administration of a tricyclic antidepressant agent.
Fluoxetine is not chemically related to any other typical antidepressive agent including tricyclic antidepressants. The antidepressant action of fluoxetine is presumed to be based on its highly specific inhibition of serotonin uptake at serotonergic reuptake sites in the brain.
Fluoxetine can also be used to assist in weight loss as disclosed in U.S. Pat. No. 4,895,845 to Seed. The causes of excess body weight and/or obesity are complex, however a common denominator in the overweight person's diet is a caloric intake which exceeds that person's body expenditures. Fluoxetine is unique as an agent for weight loss since it appears to modify the compulsion to eat in an overweight individual.
It has also been suggested that fluoxetine could be used to treat migraine headaches which are a paroxysmal disorder characterized by recurrent attacks of said headache, with or without associated visual and gastrointestinal disturbances. The cause is unknown, but evidence suggests a genetically transmitted functional disturbance of cranial circulation. Prodromal symptoms may be due to intracerebral vasoconstriction, and the head pain to dilation of scalp arteries. Migraine may occur at any age but usually beings between ages 10 and 30, more often in women than in men. Migraine headaches may be preceded by a short period of depression, irritability, restlessness or anorexia, and in some patients by scintillating scotomas, visual field defects, paresthesias, or (rarely) hemiparesis. These symptoms may disappear shortly before the headache appears or may merge with it. Pain is either unilateral or generalized. Symptoms usually follow a pattern in each patient, except that unilateral headaches may not always be on the same side. The patient may have attacks daily or only once in several months.
In addition, it has been suggested that fluoxetine could be used to treat pain, in particular chronic pain. Pain is a complex subjective phenomenon comprised of a sensation indicating real or potential tissue damage and the affective response this generates. Pain can be classified as either acute or chronic pain. Acute pain is an essential biologic signal of the potential for or the extent of injury. It is usually short-lived and is associated with hyperactivity of the sympathetic nervous system; eg, tachycardia, increased respiratory rate and blood pressure, diaphoresis, and pupillary dilation. The concurrent affect is anxiety. Treatment involves removal of the underlying etiology if possible and the use of analgesic drugs.
Chronic pain is defined as pain persisting for greater than six months. Pain of this duration loses its adaptive biologic role. Vegetative signs gradually develop; eg, lassitude, sleep disturbance, decreased appetite, loss of taste for food, weight loss, diminished libido, and constipation. A depressed affect predominates. In many patients, organic disease may be insufficient to explain the degree of pain or may be altogether absent. In these patients, as well as in many with organic disease, the psychologic factors become the primary contributor to impairment. Therapy is often difficult and prognosis is guarded.
It also has been postulated that fluoxetine is effective in the treatment of obsessive-compulsive disorders. This is a neurotic disorder characterized by the presence of recurrent ideas and fantasies (obsessions) and repetitive impulses or actions (compulsions) that the patient recognizes as morbid and toward which he feels a strong inner resistance. Anxiety is a central feature, but in contrast to the phobias (where the patient is anxious in the face of external dangers of which he perceives himself to be the passive victim), the anxiety arises in response to internally derived thoughts and urges that the patient fears he may actively carry out despite his wishes not to. Obsessive-compulsive patients comprise less than 5% of those with neurotic disorders, and about 0.05% of the population at large. The neurosis affects men and women equally and tends to be found in individuals from upper socioeconomic levels and with higher intelligence.
Furthermore, it has been suggested that fluoxetine is effective in the treatment of psychoactive substance use disorders. These disorders encompass, but are not limited to, abuse and/or dependence on alcohol, cocaine, nicotine, caffeine, and opiates (e.g. heroin, morphine) whereby drug-seeking behavior takes up a large proportion of the individual's time and resources, and results in inappropriate behavior. Psychoactive substance use disorders occur in more than 20 million people in the United States alone, and are among the most difficult conditions to treat. Fluoxetine may reduce craving, improve symptoms of depression, and result in an improved treatment outcome.
At the present time, fluoxetine is available only as a racemic mixture. That is, it is a mixture of optical isomers, called enantiomers.
The racemic mixture of fluoxetine, in addition to its use as an antidepressant and appetite suppressant, has been shown to have a wide spectrum of action which includes:
Whereas the foregoing Molloy et al. patents, in addition to the above discussed European patent application and U.S. patents, recognize compounds such as fluoxetine have optically active forms, no example of an optically active form is given. Furthermore, certain studies with the enantiomers of fluoxetine have generally concluded that there is no advantage in the use of the pure R(-)enantiomer. See, Robertson et al., J. Med. Chem., 31: pg. 1412-1417 (1988).
Various researchers have presented a limited amount of pharmacological data on the enantiomers of fluoxetine. See, Fuller et al., Pharm. Biochem. Behav., 24: pg. 281-284 (1986); Robertson et al., J. Med. Chem., 31: pg. 1412-1417 (1988); Wong et al. Drug Devel. Res. 6: pg. 397-403 (1985); Wong et al., Pharm. Biochem. Behav., 31: pg. 475-479 (1988). These references are limited by their failure to provide complete dose-response or pharmacokinetic analyses, resulting only in qualitative impressions on certain matters. The results of the above described studies are summarized in Table I below.
__________________________________________________________________________ RS R S (.+-.) (-) (+) dose ref __________________________________________________________________________ 5HT uptake cortical synaptasomes (K.sub.i) 30 33 21 nM 1 5HT uptake cortical synaptasomes (IC.sub.50) 99.5 61.5 nM 2 Inhibition of 3H-fluoxetine binding (IC.sub.50) 5.7 7.7 4.1 nM 1 Inhibition of 5HT uptake Ex Vivo brainstem (ED.sub.50) 9.3 8.7 7.4 mg/kg 1 Inhibition of PCPA effect on 5HT (full block) .about.10 .about.5 mg/kg 3 Inhibition of PCPA effect on 5HT (ED.sub.50) 2.1 1.2 mg/kg 4 Inhibition of Feeding (meal fed, 2DG) (rel. potency) R &lt; S 2 Inhibition of Saccharine palatability (ED.sub.50) 6.1 4.9 mg/kg 4 Inhibition of acetic acid writhing (ED.sub.50) 15.3 25.7 mg/kg 4 Inhibition of writhing (morphine potentiation; ED.sub.50) 3.6 5.7 mg/kg 4 Duration of 5HT uptake inhibition Ex Vivo .about.8 hr &gt;24 hr 1 Duration of Inhibition of PCPA 5HT effect .about.8 hr &gt;24 hr 3 __________________________________________________________________________ .sup.1 Wong et al 1985 .sup.2 Wong et al 1988 .sup.3 Fuller & Snoddy 1986 .sup.4 Robertson et al 1988
Briefly, the first part of the table indicates that the S(+) enantiomer is about 1.5 fold more potent in antagonizing 5HT uptake, and is probably slightly more potent in suppressing food intake. The second part of the table suggests that the R(-) enantiomer may be about 1.5 fold more potent in antagonizing pain, or potentiating morphine analgesia. The third part of the table clearly suggests that the S(+) enantiomer has a substantially greater duration of action (approximately 24 hours), than the R(-) isomer, (approximately 8 hours). Additional data published by Wong et al., Pharm. Biochem. Behav. 31: pg. 475-479 (1988) suggests that both the S(+) and R(-) forms have relatively little affinity fir 5HT.sub.1, 5HT.sub.1A, HT.sub.2, .alpha..sub.1A, .alpha..sub.2, .beta., D.sub.1, D.sub.2, H.sub.1, and M.sub.1 receptors, or the uptake of norepinephrine relative to their effect on 5HT uptake.
The racemic mixture of fluoxetine has been shown to have certain advantages over other antidepressant drugs. Antagonism of muscarinic, histaminergic and .alpha.1 adrenergic receptors has been hypothesized to be associated with various anticholinergic and cardiovascular effects of classical tricyclic antidepressant drugs. Fluoxetine binds to these and other membrane receptors from brain tissue much less potently than do these tricyclic antidepressants. Thus, fluoxetine gives less anticholinergic side effects such as blurred vision, dry mouth, constipation and urinary retention. There is also less lowering of blood pressure, tachycardia and arrhythmias.
While the racemic mixture of fluoxetine has certain advantages, it also has disadvantages. Among these disadvantages are adverse effects other than the ones described above. The most frequent reported adverse effects associated with fluoxetine are headaches, nervousness, anxiety and insomnia. These are reported by 10% to 15% of patients treated with fluoxetine. These symptoms led to drug discontinuation in 5% of the patients treated with the drug. With regard to insomnia, often patients being treated with fluoxetine must be administered sleep medication such as benzodiazepine hypnotics or sedating antidepressants in the evening to counteract the insomnia. Furthermore, fluoxetine produces a state of inner restlessness (akathisia), which is one of its more significant side effects. In all likelihood this is a result of the effect fluoxetine has on dopamine turnover in the striatum. Baldessarini et al. Arch. Gen. Psychiatry, 47 (2), pg. 191-192 (1990). It is also known that in some patients, use of fluoxetine is associated with severe anxiety leading to intense violent suicidal thoughts and self mutilation. Teicher et al., Am. J. Psychiatry, 147:2 pg. 207-210 (1990). In other patients manic behavior follows treatment with fluoxetine. Other side effects associated with fluoxetine include nausea, diarrhea, drowsiness, decrease in libido, and/or sexual dysfunction.
Another disadvantage of the racemic mixture of fluoxetine is its long half-life and long duration of action. Since the S(+) isomer of fluoxetine has a half life approximately three times that of the R(-) isomer, the long half life of the racemic mixture in all likelihood can be attributable to the amount of the S(+) isomer found in the racemic mixture. This long half life can lead to a buildup of fluoxetine in the patient's body and a concomitant increase in the above described side effects when a patient is given multiple doses.
It is therefore desirable to find a compound with the advantages of fluoxetine which would not have the above described disadvantages.